Transforming growth factor-β1 induces invasion ability of HSC-4 human oral squamous cell carcinoma cells through the Slug/Wnt-5b/MMP-10 signalling axis.

Molecular mechanism underlying the invasion of oral cancer cells remains to be clarified. We previously demonstrated that transforming growth factor-β1 (TGF-β1) induces the expression of mesenchymal markers in human oral squamous cell carcinoma HSC-4 cells. Intriguingly, the expression of the epithelial-mesenchymal transition-related transcription factor Slug was also significantly upregulated upon TGF-β1 stimulation. However, the mechanism by which Slug transduces the TGF-β1-induced signal to enhance the invasiveness of HSC-4 cells is poorly understood. Proteomic analysis revealed that the expression of matrix metalloproteinase (MMP)-10 was upregulated in TGF-β1-stimulated cells. Additionally, a Boyden chamber assay revealed that the TGF-β1-induced increase in invasiveness of HSC-4 cells was significantly inhibited by MMP-10 small interfering RNA (siRNA). Intriguingly, Slug siRNA suppressed TGF-β1-induced expression of MMP-10. These results suggest that TGF-β1 induces invasion in HSC-4 cells through the upregulation of MMP-10 expression in a Slug-dependent manner. On the other hand, Slug siRNA suppressed TGF-β1-induced Wnt-5b expression. Wnt-5b significantly induced MMP-10 expression, whereas Wnt-5b siRNA suppressed the TGF-β1-induced increase in invasiveness, suggesting that TGF-β1-induced expression of MMP-10 and the resulting upregulation of invasiveness are mediated by Wnt-5b. Overall, these results suggest that TGF-β1 stimulates HSC-4 cell invasion through the Slug/Wnt-5b/MMP-10 signalling axis.

Hino M ，Kamo M ，Saito D ，Kyakumoto S ，Shibata T ，Mizuki H ，Ishisaki A ... -  《-》

Slug is a downstream mediator of transforming growth factor-beta1-induced matrix metalloproteinase-9 expression and invasion of oral cancer cells.

Members of Snail family of transcription factors play an important role in oral cancer progression by inducing epithelial-mesenchymal transition, by promoting invasion and by increasing matrix metalloproteinase (MMP) expression. Although Snail (Snai1) is the best characterized and the most extensively studied member of this family, the role and regulation of Slug (Snai2) in oral cancer progression is less well understood. In this report, we show that transforming growth factor-beta1 (TGF-beta1) increases Slug levels in tert-immortalized oral keratinocytes and in malignant oral squamous cell carcinoma (OSCC) cells. Inhibiting ERK1/2 signaling, but not PI3-kinase signaling, blocked TGF-beta1-induced Slug expression in the malignant UMSCC1 cells. To further examine the role of Slug in OSCC progression, we generated UMSCC1 cells with inducible expression of Slug protein. Induction of Slug in UMSCC1 cells did not repress E-cadherin levels or regulate individual movement of UMSCC1 cells. Instead, Slug enhanced cohort migration and Matrigel invasion by UMSCC1 cells. Slug increased MMP-9 levels and MMP-9-specific siRNA blocked Slug-induced Matrigel invasion. Interestingly, Slug-specific siRNA attenuated TGF-beta1-induced MMP-9 expression and Matrigel invasion. These data demonstrate that TGF-beta1 increases Slug via ERK1/2 signaling, and thereby contributes to OSCC progression.

Joseph MJ ，Dangi-Garimella S ，Shields MA ，Diamond ME ，Sun L ，Koblinski JE ，Munshi HG ... -  《-》

Transforming growth factor-β1 induces epithelial-mesenchymal transition and integrin α3β1-mediated cell migration of HSC-4 human squamous cell carcinoma cells through Slug.

Saito D ，Kyakumoto S ，Chosa N ，Ibi M ，Takahashi N ，Okubo N ，Sawada S ，Ishisaki A ，Kamo M ... -  《-》

Transforming growth factor-beta 1 promotes matrix metalloproteinase-9-mediated oral cancer invasion through snail expression.

Sun L ，Diamond ME ，Ottaviano AJ ，Joseph MJ ，Ananthanarayan V ，Munshi HG ... -  《MOLECULAR CANCER RESEARCH》

Transforming growth factor-β1 suppresses bone morphogenetic protein-2-induced mesenchymal-epithelial transition in HSC-4 human oral squamous cell carcinoma cells via Smad1/5/9 pathway suppression.

Chiba T ，Ishisaki A ，Kyakumoto S ，Shibata T ，Yamada H ，Kamo M ... -  《-》